PROJECT SUMMARY There has been a reduction in breast cancer mortality in the United States in the last three decades with about 16% of women with breast cancer dying from the disease in 2017. However, racial disparities have been widened during this period. African American breast cancer patients have 42% excess mortality compared to whites. The preponderance of less favorable pathological characteristics, such as triple negative disease and high-grade tumors, coupled with individual- and health system-related disadvantages in health care access and treatment among African Americans can only partly explain this racial disparity in breast cancer mortality. Even in patients with estrogen receptor-positive breast cancer, a subtype that is considered treatable, African Americans still have about two-fold higher risk of death or relapse than their white counterparts. The genomics of late relapse in estrogen receptor-positive breast cancer is poor understood. Somatic mutations indicate the cumulative consequences of DNA damage and repair processes operative in cancer cells. The signatures of mutation processing could be important hallmarks and predictors for breast cancer relapse. Separately, there is emerging evidence that human microbiome is related to tumor immunosurveillance, is correlated with cancer therapy, has potential to be novel biomarker for prognosis, and varies by ethnic populations. In the proposed study, we will leverage an existing cohort - The Chicago Multiethnic Epidemiologic Breast Cancer Cohort (ChiMEC) ? to perform deep whole exome sequenicng (WES) of 500 well-phenotyped tumors to identify somatic mutation signatures (Aim 1). A nested case-control study design will be used with half African Americans and half Caucasians. We will investigate whether pattern of somatic mutations and mutation signatures can predict breast cancer recurrence and response to neoadjuvant chemotherapy, and whether mutation signatures are different between racial groups. We will also enhance the ChiMEC cohort by establishing a biobank of stool samples for microbiome analysis (Aim 2). In 140 patients receiving neoadjuvant chemotherapy, we will perform a Microbiome Wide Association Study (MWAS) to determine whether fecal microbial biomarkers are predictive of response to neoadjuvant chemotherapy. The goal of this application is to extend our understanding of role of tumor genomics and gut microbiota for breast cancer progression disparities, and the study findings of this project could lead to novel interventions to accelerate implementation of Precision Oncology care.